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Sci Adv. 2019 Jul 3;5(7):eaax2887. doi: 10.1126/sciadv.aax2887. eCollection 2019 Jul.

CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism.

Author information

1
Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
2
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
3
Department of Neurology, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
4
Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
5
Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.

Abstract

Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67's interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP ). We map CATACOMB's inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As CATACOMB expression is regulated through DNA methylation/demethylation, we propose CATACOMB as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.

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